OVERVIEW: What every practitioner needs to know

Are you sure your patient has bacterial gastroenteritis? What are the typical findings for this disease?

In clinical practice, diarrhea is typically defined as an increase in frequency and a decrease in consistency of the stool compared with the child’s baseline. It is the caregiver who determines that the pattern is abnormal for the child. Most episodes of infectious diarrhea resolve within 7 days and are termed "acute" or "simple." The small percentage of episodes that last more than 14 days are considered "persistent diarrhea."

Diarrhea is a common complaint among children in the United States. Most cases (~90%) are due to viruses, and therefore antibiotics are not indicated. Even among the bacterial agents, there are few indications for antimicrobial therapy. For this reason, it is rare that the practitioner faced with a patient with diarrhea will be justified in prescribing antibiotics empirically.

Nonetheless, it is important for the practitioner to be able to distinguish the small subset of patients whose diarrhea has a bacterial cause. Knowledge of the offending agent and its antibiotic susceptibility informs the practitioner whom to treat, which antibiotics are appropriate, and what clinical course and possible sequelae to anticipate. Regardless of the cause of diarrhea, the primary goal is prevention and treatment of dehydration, which is seen most commonly in infants younger than 24 months of age.

The bacterial pathogens that cause diarrhea are a heterogeneous group, but four species prevail in the United States (Shigella, nontyphoidal Salmonella, Campylobacter, and Yersinia), and will be designated as the "common bacterial pathogens" in this chapter. The clinical manifestations of the common bacterial pathogens are indistinguishable from each other. Each is capable of producing four syndromes: simple enterocolitis, dysentery, bacteremia without focal infection, and disseminated infection.

When evaluating a child with diarrhea, several features indicate that a patient is at higher than aggregate risk for having a bacterial pathogen:

Presence of diarrhea without or before onset of vomiting

A high number of diarrheal stools in a day (>3-4)

Fever

Blood in stools

Presence of fecal leukocytes

Severe crampy abdominal pain

Nonetheless, in an individual child it can be difficult to predict the cause on clinical grounds alone. Some children with bacterial diarrhea are afebrile and have watery stools without blood, and some children with viral diarrhea have fever and mucus in the stools. Clinical algorithms have been developed in an effort to identify which children are most likely to have bacterial diarrhea. In general, these algorithms have detected only a subset of children with bacterial diarrhea (range from 25%-70%, depending on the prevalence of bacterial diarrhea in the population and the algorithm used); however, when the above features are absent, it is highly unlikely that the child has bacterial diarrhea.

The dysentery syndrome requires special comment. Dysentery is a constellation of clinical signs and symptoms that are associated with severe distal colitis. Patients with dysentery characteristically present with a high frequency of small-volume stools containing blood, pus, and mucus, passed with urgency and straining during defecation, often in association with fever and abdominal cramps. Watery diarrhea may precede the onset of dysentery.

Shigella is the major cause of bacillary dysentery. The diarrheal illness associated with Shiga toxin-producing Escherichia coli (STEC), also known as enterohemorrhagic E. coli, also can begin with watery stools. The stools usually become bloody in 1-3 days; however, the bloody stools tend to be more voluminous in STEC infection compared with those seen in bacterial dysentery. Severe abdominal pain is common in STEC infection, but most children are afebrile.

The colitis associated with Clostridiumdifficile shares many of the features seen with the common bacterial enteropathogens. Occasionally, severe cases produce little or no diarrhea, especially in the presence of ileus or toxic megacolon.

In some patients, particularly infants younger than 3 months of age, and those with underlying conditions (immunodeficiency, malnutrition, hemolytic anemia, chronic colitis, prosthetic devices, or liver disease), the common bacterial enteropathogens produce invasive infections such as bacteremia with or without clinical enteritis. Nontyphoidal Salmonella is the most frequent offending agent. In approximately 10% of patients with bacteremia, extraintestinal sites are seeded, resulting in focal infections (osteomyelitis, pneumonia, meningitis, tissue abscesses). Rarely, contiguous spread from the intestine produces cholangitis, pancreatitis, appendicitis, or peritonitis after intestinal perforation. HIV-infected individuals are prone to the development of persistent or recurrent bacteremia.

Symptoms include the following:

Fever

Blood in stool

Vomiting

What other disease/condition shares some of these symptoms?

Diarrhea can sometimes accompany nonintestinal infections (e.g., urinary tract infection, otitis media) and can be result from a multitude of noninfectious causes, including malabsorption and disorders affecting intestinal transit time. Inflammatory bowel disease and proctitis are inflammatory conditions that may mimic bacterial gastroenteritis. Entamoeba histolytica should be considered in a child with dysentery who has travelled to an endemic area.

What caused this disease to develop at this time?

Four “common” enteropathogens are responsible for most bacterial diarrhea acquired in the United States: Shigella, non-typhoidal Salmonella,
Campylobacter, and Yersinia. The diarrheagenic E. coli encountered most frequently (albeit uncommonly) in the United States are STEC, enteroaggregative E. coli (EAEC), and enterotoxigenic E. coli (ETEC). C. difficile colitis is unusual in children but should be considered in certain clinical settings. Although the data are conflicting, many experts believe that Aeromonas can cause diarrhea and dysentery. Vibrio species share an ecologic niche with Aeromonas and are occasionally identified in cases of diarrhea.

Simple epidemiologic sleuthing can provide clues to the diagnosis. The common bacterial diarrheas (plus Aeromonas) generally show distinct seasonality, with a peak in the late summer and autumn for all but Yersinia, which peaks in wintertime. Many agents have age predilections. The incidence of nontyphoidal Salmonella is highest in infancy, Shigella is most common in preschoolers (1-4 years), STEC is seen most often in school-aged children (5-9 years), whereas Campylobacter shows no clear age predisposition in childhood. Although asymptomatic carriage may be common, there is little evidence that children younger than 2 years are susceptible to C. difficile colitis.

The very low infectious dose of Shigella allows fecal-oral spread to occur readily, particularly in environments in which sanitation and hygiene are suboptimal, such as day care centers and custodial institutions.

Nontyphoidal Salmonella is the leading bacterial cause of foodborne outbreaks, with the most common vehicles being eggs and chicken. Transovarian passage of
Salmonella occurs in hens, so grade A eggs with intact shells can harbor the organism. Salmonella from these sources can be ingested in improperly cooked foods or can be inoculated onto grocery packaging, kitchen surfaces, utensils, and other foods, and cross-infect foods prepared for infants and children. Pet reptiles (turtles, lizards, or snakes) colonized asymptomatically with Salmonella serve as another vehicle for infection.

Campylobacter species infect a wide range of domestic and wild birds and animals. Infections among hikers who drink untreated surface water contaminated with the feces of infected birds and animals are well documented. However, most human infections are sporadic and related to ingestion of contaminated poultry. Unpasteurized milk and contaminated water are the most common vehicles identified in outbreaks. Unlike Salmonella, there is no transovarian passage of Campylobacter in hens, making eggs an uncommon source. Cats and dogs develop symptomatic Campylobacter infection that can be transmitted to humans.

Yersinia is classically associated with consumption or preparation of contaminated pork. Yersinia is cold tolerant, with winter seasonality and sustained infectivity in refrigerated blood products. Transmission from sick pets has also been reported.

ETEC contaminates food and water sources in developing countries and should be suspected in a child in who watery diarrhea develops in relation to travel to an endemic area. STEC, notably the most virulent serotype, known as O157:H7, is an occasional cause of diarrhea outbreaks as well as sporadic cases. STEC is excreted asymptomatically by cattle, particularly in the northern tier states. Exposure to cattle manure or food or water contaminated thereby, may lead to human infections. Undercooked beef is the most common vehicle, but vegetables and fruits are increasingly implicated, and contact with fresh water contaminated with manure, or exposure to infected animals, humans, or contaminated fomites also pose a risk.

The infectious dose for O157:H7 is similar to that of Shigella species, and person-to-person transmission is noted in nearly all large outbreaks of the infection. The presence of bloody diarrhea and hematologic complications (see below) should raise suspicion.

C. difficile usually occurs in patients with underlying medical conditions and recent antibiotic exposure and is frequently hospital acquired.

Infection with Aeromonas and Vibrio species should be suspected when there has been recent (usually within 3 days) exposure to natural marine environments or seafood or in cases of traveler’s diarrhea.

In aggregate, the epidemiologic features that are most likely to help the practitioner arrive at the correct diagnosis include season; age; recent travel to a developing country; drinking surface water or swimming in natural aquatic environments; day care attendance; ill contacts; underlying medical conditions; a visit to a farm or petting zoo or contact with reptiles, birds, or pets with diarrhea; consumption of unsafe foods (e.g., raw meats, eggs, or shellfish or unpasteurized milk or juices); recent hospitalization; or antibiotic use.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The definitive test to detect the presence of bacterial gastroenteritis remains the culture of enteropathogens from the stool. In most clinical laboratories, the standard stool culture identifies Shigella, Salmonella, Campylobacter, and
Yersinia. Specialized testing is required if other agents are suspected, as discussed below.

Stool cultures are often viewed as having a high cost per relative yield, so efforts have been made to define the clinical scenarios where the yield is likely to be the highest. Although no approach is completely satisfactory, if any of the clinical features predictive of bacterial diarrhea are present (no preceding vomiting, frequent stools, hematochezia, fecal leukocytes, and abdominal cramps, as discussed above), it is justifiable to send stool for culture. An additional indication for a stool culture is to evaluate persistent diarrhea. Blood cultures should be obtained in ill-appearing or high-risk patients.

One approach to reducing performance of stool cultures in hospitalized children that have a very low yield is the “3-day rule.” Unless overriding circumstances prevail (e.g., admission specimens were not sent, the patient has AIDS, or a nosocomial outbreak is suspected), routine stool cultures should not be requested from patients hospitalized for greater than 3 days. Conversely, this same set of patients should have specimens tested for C. difficile toxins especially if they are severely ill, or have fever, tenesmus, or bloody diarrhea.

There are effective ways to increase the yield of stool cultures in children with bacterial diarrhea. Yield from culture of a single stool is greater than 70%, but even the most experienced clinical laboratories may fail to isolate the offending pathogen. Whether this is due to intermittent or self-limiting excretion or the difficulty in finding a bacterium in the context of abundant commensal microbiota is unclear. In any case, a highly skilled clinical laboratory should be used, and in cases of high suspicion, multiple stools may increase yield.

The clinician also can improve the yield of stool cultures by attending to the conditions of collection and transport. Every effort should be made to obtain the specimen before the administration of antibiotics and to expeditiously transport the specimen to the laboratory, using transport media if possible. Shigella, for example, are fastidious organisms that do not survive well in stool allowed to remain at room temperature. If a whole stool is not available, obtain a rectal swab for culture, as the yield is very good.

The fecal leukocyte examination can be used to assess the likelihood that a patient’s diarrhea is due to a bacterial pathogen. The presence of leukocytes indicates an inflammatory syndrome that is overall more likely due to a common bacterial infection. In contrast, fecal leukocytes are absent or sparse in patients with STEC infection.

There are studies suggesting that the yield for Campylobacter diagnostics is enhanced by use of an immunoassay in addition to or instead of conventional culture.

If STEC infection is suspected, the most common serotype (O157:H7) can be detected in most clinical laboratories using culture on MacConkey agar containing sorbitol. Sorbitol-negative (nonfermenting) E. coli should be serotyped to confirm the presence of
E. coli O157:H7. Commercial tests for the identification of Shiga toxin are also available, which have the advantage of leading to the identification of non-O157:H7 STEC, but should not be substituted for culture.

If suspicion is high and point-of-care testing is negative or inconclusive, specimens can be sent to the state health laboratory for definitive diagnosis. Yield of stool culture for the pathogen drops dramatically after the seventh day of infection. Patients with STEC infection should be carefully monitored with a complete blood cell count with smear, platelet count, blood urea nitrogen level, and creatinine concentrations to detect changes suggestive of the hemolytic uremic syndrome (HUS). Diagnosis of ETEC and EAEC is possible only in research laboratories.

The laboratory diagnosis of C. difficile infection requires demonstration of
C. difficile toxin or toxigenic C. difficile. Because asymptomatic carriage with C. difficile can occur, a positive toxin assay does not prove pathogenicity. Endoscopy should be considered in children with evidence of inflammatory colitis to look for evidence of pseudomembranous colitis. A number of tests are commercially available to detect toxin-producing C. difficile in stool, including enzyme immunoassays for toxins A and B, cell culture cytotoxicity assay, and polymerase chain reaction (PCR). The sensitivity of cell culture and PCR are superior to that of immunoassay.

Would imaging studies be helpful? If so, which ones?

Imaging studies have limited utility in the evaluation of a child with suspected bacterial enteritis with one exception. If an extraintestinal infection is suspected, CT or magnetic resonance imaging may assist with diagnosis and management decisions.

If you are able to confirm that the patient has bacterial gastroenteritis, what treatment should be initiated?

General principles: Prevention of dehydration and correction of fluid and electrolyte losses, preferably by oral rehydration, is the mainstay of treatment for all bacterial diarrhea. Children who are not dehydrated should be offered ample quantities of appropriate fluids to prevent dehydration from occurring. An age-appropriate unrestricted diet is recommended as soon as dehydration is corrected. Continued feeding not only prevents nutritional deficiency but can also actually shorten the duration of the illness.

Antiemetic and antimotility agents: These should generally be avoided. Note that fluoroquinolones are effective in the treatment of many cases of bacterial diarrhea, as described below; however, these drugs are not approved for the treatment of diarrhea in children younger than 18 years and should be chosen only if the benefits outweigh the risks.

Shigella: Although most episodes of shigellosis are self-limited, antibiotics can shorten the duration of illness and fecal excretion. Treatment is recommended for patients with severe disease, dysentery, or immunodeficiency, or to prevent spread of infection. Agents of proven benefit include ampicillin (not amoxicillin) and trimethoprim-sulfamethoxazole (although antibiotic resistance to these agents is now common in the United States). Extended-spectrum cephalosporins (e.g., ceftriaxone), ciprofloxacin, and azithromycin are also effective. Except in severe cases, a 5-day course of oral antibiotics is sufficient.

Nontyphoidal Salmonella: Antibiotic therapy is not indicated for otherwise healthy children with simple gastroenteritis caused by nontyphoidal Salmonella because therapy does not shorten the course of the disease and may prolong fecal excretion. Although of unproven benefit, treatment of children with simple enterocolitis who are at increased risk of invasive disease (described above) is generally recommended. Ampicillin and trimethoprim-sulfamethoxazole are good choices for susceptible strains. Extended-spectrum cephalosporins, azithromycin, and fluoroquinolones are alternatives if resistance to first-line drugs is suspected or proved.

Bacteremia without focal infection: This condition is generally treated for 10-14 days, although the route of administration and duration of therapy can be adjusted according to the clinical presentation and underlying health status of the child. Children with localized invasive disease (osteomyelitis, pneumonia, abscess, meningitis, or bacteremia in HIV-infected patients) should receive empirical therapy with expanded-spectrum cephalosporins or fluoroquinolones until susceptibility results become available. Treatment should continue for at least 4 weeks (6 weeks for meningitis).

Aminoglycosides should not be used to treat nontyphoidal Salmonella infection even if in vitro testing indicates susceptibility. Occasionally, treatment failures have been reported with cephalosporins despite in vitro susceptibility.

Campylobacter: Oral macrolide agents have been shown to benefit some patients with Campylobacter infection when administered in the first days of illness. Aminoglycosides plus an intestinally active agent such as an extended-spectrum cephalosporin or carbapenem (e.g., meropenem) are often used to treat invasive infections until results of antibiotic susceptibility testing become available.

Yersinia: The efficacy of antibiotics in the treatment of simple enteritis and pseudoappendicitis syndrome caused by Yersinia species is unproved. Invasive infections should be treated with antibiotics; most strains are susceptible to trimethoprim-sulfamethoxazole, aminoglycosides, extended-spectrum β-lactams, and fluoroquinolones.

STEC and ETEC: Antibiotics should not be given to treat STEC infection because there is no known benefit, and some studies have suggested an increased risk of HUS. In addition, antimotility agents, narcotics, and nonsteroidal antiinflammatory drugs should not be given to patients with acute infection.

Volume expansion with normal saline may provide some benefit to infected patients, and dehydration should be carefully avoided. Patients with severe watery diarrhea after travel to a resource-poor country can be offered azithromycin or fluoroquinolones for empirical treatment of ETEC (although most ETEC infections are brief and self-limited and typically resolve before the traveler returns to the United States). EAEC infections do not require antibiotic treatment.

C. difficile: Treatment should be considered for moderate or severe diarrhea or colitis attributed to C. difficile. The precipitating antibiotic should be discontinued. Metronidazole (oral or intravenous) is usually first-line therapy. Oral vancomycin is indicated if disease is severe (requiring intensive care, pseudomembranous colitis diagnosed by endoscopy, or underlying intestinal disease) or for patients who do not respond to metronidazole.

What are the adverse effects associated with each treatment option?

Licensed antibiotics can be associated with a wide range of adverse effects. Although most are mild, severe, life-threatening reactions can occur, such as anaphylaxis. For this reason, we have tried to limit treatment recommendations to those instances in which evidence suggests a favorable risk to benefit ratio.

What are the possible outcomes of bacterial gastroenteritis?

The prognosis of bacterial diarrhea is generally excellent. Most episodes in otherwise healthy children resolve spontaneously in 7-10 days. In a small percentage (<10%), diarrhea can become persistent, requiring careful management of the child’s fluid and dietary intake. In contrast, the prognosis can be guarded, even in the presence of appropriate antibiotics, when high-risk children become infected, particularly with nontyphoidal Salmonella. Examples include nontyphoidal Salmonella osteomyelitis in children with sickle cell anemia (which can result in chronic or recurrent disease and growth impairment) and meningitis in infants younger than 3 months of age (which has high morbidity and mortality). Pathogen-specific complications or sequelae are discussed below.

What causes this disease and how frequent is it?

Diarrhea is one of the most common illnesses affecting children. During each of the first 2 years of life, an infant living in the United States can be expected to experience 1-3 episodes of diarrhea. In the United States, acute diarrhea accounts for moret than 1.5 million outpatient visits, 200,000 hospitalizations, and approximately 300 deaths/year. Bacterial agents are responsible for 5%-10% of these episodes. In 2010, the Centers for Disease Control and Prevention estimated the incidence of laboratory-diagnosed bacterial infections based on surveillance performed by the Foodborne Diseases Active Surveillance Network per 100,000 children younger than 5 years of age as follows: Salmonella, 69.5; Campylobacter, 24.4; Shigella, 16.4; STEC, 8.3; Yersinia, 1.9; and Vibrio 0.0.

How do these pathogens/genes/exposures cause the disease?

The invasive bacterial pathogens (Shigella, Salmonella, Yersinia, Campylobacter) cause disease by colonization and invasion of the intestinal mucosa, followed by the infiltration of leukocytes and the opening of intestinal tight junctions. The precise cause of the net secretory state manifested clinically as diarrhea remains obscure, although inflammation per se as well as altered intestinal permeability are established causes of the secretory state. The presence of specific enterotoxins has long been posited but never proved for these pathogens.

Several noninvasive bacterial pathogens share the pathogenic paradigm of attaching to the intestine and elaborating potent enterotoxins. STEC adhere intimately to the colonic mucosa and transduce a secretogenic signal mediated by the transepithelial injection of several protein toxins. Shiga toxin itself appears to be inflammatory and secretogenic and may exacerbate diarrhea in addition to targeting epithelial cells and producing vascular damage, which lead to hemorrhagic colitis, and in some children a prothrombotic state that proceeds to HUS.

ETEC adhere to the small intestinal mucosa by colonizing fimbriae and elaborate secretory toxins: heat-labile toxin or heat-stable toxin, or both. Cholera toxin produced by
Vibrio cholerae is very similar to heat-labile toxin. The pathogenesis of C. difficile–associated diarrhea includes alteration of the colonic microflora (usually, but not always, after antibiotic therapy), overgrowth of C. difficile and toxin production (necessary but not sufficient), plus mucosal injury, inflammation, and diarrhea.

Other clinical manifestationsthat might help with diagnosis and management

Yersinia is notorious for causing pseudoappendicitis in older children and adults that has been attributed to mesenteric adenitis. A syndrome of exudative pharyngitis and cervical adenitis also has been linked to Yersinia.

What complications might you expect from the disease or treatment of the disease?

The major complication of diarrheal disease from any cause is dehydration. Signs of dehydration include dry mouth, decreased urination, increased thirst, sunken eyes, and decreased skin turgor. When severe, lethargy and cardiovascular instability ensue.

Salmonella, Shigella, Campylobacter, and Yersinia are all capable of producing reactive arthritis, either alone or in association with conjunctivitis and uveitis. This postinfectious sequela is primarily a disease of adults and is exceedingly rare in children. Arthritis begins acutely usually 2-4 weeks after the intestinal illness. Joint symptoms range from mild arthralgia to severe polyarthritis and become chronic in about 10% of cases. Individuals with the HLA-B27 histocompatibility antigen are predisposed, accounting for approximately one half of the cases. The risk to the remaining 92%-99% of the population that is HLA B27 negative is thus very low.

HUS occurs in about 2%-8% of children younger than 10 years of age infected with STEC. Predictors for the development of this syndrome are incompletely understood, although those with more severely inflammatory enteritis (evidenced by a high peripheral white blood cell count) are thought to be at increased risk. Patients infected with STEC are also at risk for cerebrovascular accident and toxic megacolon. Case fatality is approximately 2%-3%. Insufficient data are available to determine the long-term renal function in those who survive. Patients with proven STEC infection should be observed carefully (as outpatients in most cases); the HUS risk period is past when the platelet count rises, or if the platelet count is stable and diarrhea is resolved or resolving.

Intestinal complications of shigellosis include toxic megacolon, rectal prolapse, and protein-losing enteropathy. These are rare complications in developed countries, where patients are generally well nourished and present to medical attention before these serious sequelae arise. A variety of extraintestinal manifestations may occur. The most common is seizures, usually in febrile children without associated encephalopathy.

Because Shigella dysenteriae serotype 1 harbors the phage encoding Shiga toxin, patients with this infection are prone to the development of HUS, although antibiotic therapy does not appear to increase its risk. Shigella sepsis is uncommon and is usually seen in hosts with malnutrition or immunodeficiency. Persistent diarrhea and malnutrition are the most common chronic sequelae seen in children from developing countries.

Guillain-Barré syndrome is a known complication of Campylobacter gastroenteritis. One study estimated that about 30% of episodes of Guillain-Barré syndrome have a preceding Campylobacter infection. The neurologic manifestations begin 10-21 days after the onset of diarrhea. Molecular mimicry has been incriminated as the cause, resulting from cross-reactivity between bacterial lipooligosaccharide epitopes and GM1 gangliosides on the surface of host neural tissues. No management approach has been shown to mitigate the risk. Advice to the patient with proven Campylobacter infection as to the signs and symptoms of this syndrome is prudent.

How can bacterial gastroenteritis be prevented?

Consumption of contaminated food poses the greatest risk for bacterial gastroenteritis. Parents should be counseled routinely about safe food handling and preparation, as well as hygienic practices when handling pet chicks, reptiles, cats, and dogs (see http://www.cdc.gov/salmonella/general/prevention.html). Small children should not be permitted to handle raw meats in the grocery cart or assist with the preparation of meat or poultry before cooking, and eggs, chicken, beef, pork, and seafood should be thoroughly cooked before consumption.

Beef poses a particular hazard. Hamburger and beef steaks should be served well done (internal temperature at least 155°F). Hikers should bring ample supplies of clean water to obviate the need to drink untreated surface water. Fecal oral hygiene should always be practiced on exposure to any other person with diarrhea. When traveling to developing countries, children should only consume food that is cooked and served steaming hot, and drink only hot, bottled, or canned beverages.

Ongoing controversies regarding etiology, diagnosis, treatment

The optimal management of simple Salmonella enterocolitis in infants and those with underlying conditions is not known. It is difficult to reconcile the lack of benefit associated with treating simple enterocolitis in otherwise healthy individuals with the known risks of treatment in that population (prolonged excretion and increased risk of relapse), and the increased risk of invasive disease in high-risk individuals. Most experts will obtain blood cultures in these high-risk individuals and begin empirical treatment. The route and duration of treatment can be adjusted according to the results of the cultures, the organism’s susceptibility, and the child’s response to therapy.

Another area of controversy is whether antibiotics should be used to treat STEC. A 2002 meta-analysis implied that antibiotic therapy of E. coli O157:H7 infections might not be harmful. However, this conclusion has been questioned on methodologic grounds and the consensus of experts is that antibiotics may increase the risk of HUS and should not be used.